687 - Expanding Phenotypic Characterization of Patients with COL4A1/2 Mutation

Publication Number: 2670.687

Mackenzie Buls, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States; Usha Nagaraj, Cincinnati Children's Hospital Medical Center, cincinnati, OH, United States; Charu Venkatesan, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States

Background: COL4A1 and COL4A2, which encode type IV α1 and α2 collagen chains, respectively, are essential for structural integrity for vascular basement membranes. Reported brain findings include porencephaly, schizencephaly, diffuse leukoencephalopathy, intracranial aneurysms and intracranial hemorrhage. With expansion of genetic testing, it is likely that novel imaging and clinical phenotypes will be identified.

Objective: Analyze MRI findings, clinical phenotypes and outcomes of patients with genetically confirmed COL4A1/2 mutations.

Design/Methods: IRB-approved, retrospective chart review study of all cases of COL4A1/2 who had postnatal follow up data at Cincinnati Children’s Hospital from 2010-2023.

Results: Fourteen patients (age range: 3 to 31 years ) with COL4A1 or COL4A2 mutations were identified (9: COL4A1 and 5: COL4A2 mutations).  Four had fetal MRI scans. Findings included signs of germinal matrix hemorrhage (n=4; 2: hemorrhage; 2: porencephalic changes), vermian hypoplasia (n=2), cerebellar hemisphere anomalies (n=2), Blake Pouch Cyst (n=3), ventriculomegaly (n=3), suspected neuronal migration anomaly (n=1), white matter hyperintensity (n=1), and absent septum pellucidum (n=1). Importantly, none of the cases had findings suggestive of frontal lobe involvement as previously described in the literature. Post-natal imaging findings (n=14) included white matter gliosis, white matter volume loss, microhemorrhages, thin corpus callosum, delayed myelination, ventriculomegaly, cerebellar abnormality, and absent septum pellucidum. Epilepsy was present in 50% of patients (average age of onset: 14 months). 64% of patients were ambulatory and 28.6% were non-ambulatory. Language was appropriate in 42.8% and 50% of patients were fully independent with regards to performing activities of daily living.

Conclusion(s): Prenatal MRI findings suggestive of germinal matrix hemorrhage should raise suspicion for COL4A mutation. In addition to features classically described in the literature, our study found a higher prevalence of posterior fossa anomalies and white matter volume loss. Additionally, delayed myelination was observed postnatally, suggesting broader developmental white matter vulnerability. These results highlight a broader spectrum of structural abnormalities associated with COL4A1 and COL4A2 mutations.

Fetal and postnatal imaging of patients with COL4A mutation.
Figure 1-COL4A1:2.pdfFigure 1a and 1b: Axial T2-SSFSE image of the brain in a 22 week gestational age fetus (a) demonstrates a left germinal matrix hemorrhage (black arrow) with ventriculomegaly of the left lateral ventricle. Axial T2-FSE image of the brain in the same patient at 4 years of age (b) demonstrates resultant left porencephalic change (black arrow).

Figure 1c and 1d: Axial T2-SSFSE image of the brain in a 34 week 4 day gestational age fetus (c) demonstrates bilateral ventriculomegaly with superimposed left porencephalic change without visible blood products (black arrow). Axial T2-FSE image of the brain in the same patient at 7 months of age (d) demonstrates similar but persistent appearance of left porencephalic change (black arrow).

Figure 1e and 1f: Axial T2-SSFSE image of the brain in a 28 week 3 day gestational age fetus(e) demonstrates right ventriculomegaly with suspected right perisylvian neuronal migrational anomaly (white arrow) marked by asymmetric widening of the right sylvian fissure. Axial T2-FSE image of the brain in the same patient at 6 weeks of age (f) demonstrates right porencephalic changes (white arrow) without co-existing neuronal migrational anomaly.